Risk of intracranial hemorrhage with direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials

We performed a systematic review and meta-analysis to compare the risk of intracranial hemorrhage (ICH) between direct oral anticoagulants (DOACs) and other antithrombotic drugs in detail across all diseases. PubMed, EMBASE, Web of Science, and the Cochrane Library were searched for relevant randomized controlled trials (RCTs). Heterogeneity was examined using the I2 statistic. Risk ratio (RR) and 95% confidence interval (CI) were calculated using random-effects meta-analysis. Fifty-five RCTs were included in this meta-analysis. Compared with vitamin K antagonists (VKAs), dabigatran reduced the risk of ICH by 60% (RR 0.40; 95% CI 0.28–0.57), apixaban by 57% (RR 0.43; 95% CI 0.31–0.58), edoxaban by 56% (RR 0.44; 95% CI 0.29–0.67) and rivaroxaban by 41% (RR 0.59; 95%CI 0.44–0.80). Compared with low-molecular-weight heparins (LMWHs), apixaban, edoxaban and rivaroxaban had a similar risk of ICH. Compared with aspirin, dabigatran and apixaban had a similar risk of ICH, while rivaroxaban posed an increased risk of ICH (RR 2.12; 95% CI 1.31–3.44). For secondary prevention stroke, DOACs reduced the risk of ICH by 46% compared with warfarin (RR 0.54; 95% CI [0.42–0.70]) and had a similar risk of ICH compared with aspirin. All DOACs had a lower risk of ICH than VKAs. In terms of the risk of ICH, DOACs were overall as safe as LMWHs, and apixaban and dabigatran were as safe as aspirin, but rivaroxaban was not. For secondary prevention stroke, the risk of ICH with DOACs was overall lower than warfarin and similar to aspirin, but it should be noted that compared with aspirin, rivaroxaban may increase the risk of ICH. This is the first pair-wise meta-analysis that compares the risk of ICH between DOACs and other antithrombotic drugs in detail across all diseases, which may have certain significance for patients with high risk of ICH to choose antithrombotic drugs in clinical practice.